Evaluation of a novel approach to community health care delivery in Ifanadiana District, Madagascar.

Despite widespread adoption of community health (CH) systems, there are evidence gaps to support global best practice in remote settings where access to health care is limited and community health workers (CHWs) may be the only available providers. The nongovernmental health organization Pivot partnered with the Ministry of Public Health (MoPH) to pilot a new enhanced community health (ECH) model in rural Madagascar, where one CHW provided care at a stationary CH site while additional CHWs provided care via proactive household visits. The program included professionalization of the CHW workforce (i.e., targeted recruitment, extended training, financial compensation) and twice monthly supervision of CHWs. For the first eighteen months of implementation (October 2019-March 2021), we compared utilization and proxy measures of quality of care in the intervention commune (local administrative unit) and five comparison communes with strengthened community health programs under a different model. This allowed for a quasi-experimental study design of the impact of ECH on health outcomes using routinely collected programmatic data. Despite the substantial support provided to other CHWs, the results show statistically significant improvements in nearly every indicator. Sick child visits increased by more than 269.0% in the intervention following ECH implementation. Average per capita monthly under-five visits were 0.25 in the intervention commune and 0.19 in the comparison communes (p<0.01). In the intervention commune, 40.3% of visits were completed at the household via proactive care. CHWs completed all steps of the iCCM protocol in 85.4% of observed visits in the intervention commune (vs 57.7% in the comparison communes, p-value<0.01). This evaluation demonstrates that ECH can improve care access and the quality of service delivery in a rural health district. Further research is needed to assess the generalizability of results and the feasibility of national scale-up as the MoPH continues to define the national community health program.

Applying a zero-corrected, gravity model estimator reduces bias due to heterogeneity in healthcare utilization in community-scale, passive surveillance datasets of endemic diseases.

Data on population health are vital to evidence-based decision making but are rarely adequately localized or updated in continuous time. They also suffer from low ascertainment rates, particularly in rural areas where barriers to healthcare can cause infrequent touch points with the health system. Here, we demonstrate a novel statistical method to estimate the incidence of endemic diseases at the community level from passive surveillance data collected at primary health centers. The zero-corrected, gravity-model (ZERO-G) estimator explicitly models sampling intensity as a function of health facility characteristics and statistically accounts for extremely low rates of ascertainment. The result is a standardized, real-time estimate of disease incidence at a spatial resolution nearly ten times finer than typically reported by facility-based passive surveillance systems. We assessed the robustness of this method by applying it to a case study of field-collected malaria incidence rates from a rural health district in southeastern Madagascar. The ZERO-G estimator decreased geographic and financial bias in the dataset by over 90% and doubled the agreement rate between spatial patterns in malaria incidence and incidence estimates derived from prevalence surveys. The ZERO-G estimator is a promising method for adjusting passive surveillance data of common, endemic diseases, increasing the availability of continuously updated, high quality surveillance datasets at the community scale.

Climatic, land-use and socio-economic factors can predict malaria dynamics at fine spatial scales relevant to local health actors: Evidence from rural Madagascar.

While much progress has been achieved over the last decades, malaria surveillance and control remain a challenge in countries with limited health care access and resources. High-resolution predictions of malaria incidence using routine surveillance data could represent a powerful tool to health practitioners by targeting malaria control activities where and when they are most needed. Here, we investigate the predictors of spatio-temporal malaria dynamics in rural Madagascar, estimated from facility-based passive surveillance data. Specifically, this study integrates climate, land-use, and representative household survey data to explain and predict malaria dynamics at a high spatial resolution (i.e., by Fokontany, a cluster of villages) relevant to health care practitioners. Combining generalized linear mixed models (GLMM) and path analyses, we found that socio-economic, land use and climatic variables are all important predictors of monthly malaria incidence at fine spatial scales, via both direct and indirect effects. In addition, out-of-sample predictions from our model were able to identify 58% of the Fokontany in the top quintile for malaria incidence and account for 77% of the variation in the Fokontany incidence rank. These results suggest that it is possible to build a predictive framework using environmental and social predictors that can be complementary to standard surveillance systems and help inform control strategies by field actors at local scales.

Analytical framework to evaluate and optimize the use of imperfect diagnostics to inform outbreak response: Application to the 2017 plague epidemic in Madagascar.

During outbreaks, the lack of diagnostic "gold standard" can mask the true burden of infection in the population and hamper the allocation of resources required for control. Here, we present an analytical framework to evaluate and optimize the use of diagnostics when multiple yet imperfect diagnostic tests are available. We apply it to laboratory results of 2,136 samples, analyzed with 3 diagnostic tests (based on up to 7 diagnostic outcomes), collected during the 2017 pneumonic (PP) and bubonic plague (BP) outbreak in Madagascar, which was unprecedented both in the number of notified cases, clinical presentation, and spatial distribution. The extent of these outbreaks has however remained unclear due to nonoptimal assays. Using latent class methods, we estimate that 7% to 15% of notified cases were Yersinia pestis-infected. Overreporting was highest during the peak of the outbreak and lowest in the rural settings endemic to Y. pestis. Molecular biology methods offered the best compromise between sensitivity and specificity. The specificity of the rapid diagnostic test was relatively low (PP: 82%, BP: 85%), particularly for use in contexts with large quantities of misclassified cases. Comparison with data from a subsequent seasonal Y. pestis outbreak in 2018 reveal better test performance (BP: specificity 99%, sensitivity: 91%), indicating that factors related to the response to a large, explosive outbreak may well have affected test performance. We used our framework to optimize the case classification and derive consolidated epidemic trends. Our approach may help reduce uncertainties in other outbreaks where diagnostics are imperfect.

Impact of health system strengthening on delivery strategies to improve child immunisation coverage and inequalities in rural Madagascar.

BACKGROUND: To reach global immunisation goals, national programmes need to balance routine immunisation at health facilities with vaccination campaigns and other outreach activities (eg, vaccination weeks), which boost coverage at particular times and help reduce geographical inequalities. However, where routine immunisation is weak, an over-reliance on vaccination campaigns may lead to heterogeneous coverage. Here, we assessed the impact of a health system strengthening (HSS) intervention on the relative contribution of routine immunisation and outreach activities to reach immunisation goals in rural Madagascar. METHODS: We obtained data from health centres in Ifanadiana district on the monthly number of recommended vaccines (BCG, measles, diphtheria, tetanus and pertussis (DTP) and polio) delivered to children, during 2014-2018. We also analysed data from a district-representative cohort carried out every 2 years in over 1500 households in 2014-2018. We compared changes inside and outside the HSS catchment in the delivery of recommended vaccines, population-level vaccination coverage, geographical and economic inequalities in coverage, and timeliness of vaccination. The impact of HSS was quantified via mixed-effects logistic regressions. RESULTS: The HSS intervention was associated with a significant increase in immunisation rates (OR between 1.22 for measles and 1.49 for DTP), which diminished over time. Outreach activities were associated with a doubling in immunisation rates, but their effect was smaller in the HSS catchment. Analysis of cohort data revealed that HSS was associated with higher vaccination coverage (OR between 1.18 per year of HSS for measles and 1.43 for BCG), a reduction in economic inequality, and a higher proportion of timely vaccinations. Yet, the lower contribution of outreach activities in the HSS catchment was associated with persistent inequalities in geographical coverage, which prevented achieving international coverage targets. CONCLUSION: Investment in stronger primary care systems can improve vaccination coverage, reduce inequalities and improve the timeliness of vaccination via increases in routine immunisations.

Geographic barriers to care persist at the community healthcare level: Evidence from rural Madagascar.

Geographic distance is a critical barrier to healthcare access, particularly for rural communities with poor transportation infrastructure who rely on non-motorized transportation. There is broad consensus on the importance of community health workers (CHWs) to reduce the effects of geographic isolation on healthcare access. Due to a lack of fine-scale spatial data and individual patient records, little is known about the precise effects of CHWs on removing geographic barriers at this level of the healthcare system. Relying on a high-quality, crowd-sourced dataset that includes all paths and buildings in the area, we explored the impact of geographic distance from CHWs on the use of CHW services for children under 5 years in the rural district of Ifanadiana, southeastern Madagascar from 2018-2021. We then used this analysis to determine key features of an optimal geographic design of the CHW system, specifically optimizing a single CHW location or installing additional CHW sites. We found that consultation rates by CHWs decreased with increasing distance patients travel to the CHW by approximately 28.1% per km. The optimization exercise revealed that the majority of CHW sites (50/80) were already in an optimal location or shared an optimal location with a primary health clinic. Relocating the remaining CHW sites based on a geographic optimum was predicted to increase consultation rates by only 7.4%. On the other hand, adding a second CHW site was predicted to increase consultation rates by 31.5%, with a larger effect in more geographically dispersed catchments. Geographic distance remains a barrier at the level of the CHW, but optimizing CHW site location based on geography alone will not result in large gains in consultation rates. Rather, alternative strategies, such as the creation of additional CHW sites or the implementation of proactive care, should be considered.

Geographic barriers to establishing a successful hospital referral system in rural Madagascar.

BACKGROUND: The provision of emergency and hospital care has become an integral part of the global vision for universal health coverage. To strengthen secondary care systems, we need to accurately understand the time necessary for populations to reach a hospital. The goal of this study was to develop methods that accurately estimate referral and prehospital time for rural districts in low and middle-income countries. We used these estimates to assess how local geography can limit the impact of a strengthened referral programme in a rural district of Madagascar. METHODS: We developed a database containing: travel speed by foot and motorised vehicles in Ifanadiana district; a full mapping of all roads, footpaths and households; and remotely sensed data on terrain, land cover and climatic characteristics. We used this information to calibrate estimates of referral and prehospital time based on the shortest route algorithms and statistical models of local travel speed. We predict the impact on referral numbers of strategies aimed at reducing referral time for underserved populations via generalised linear mixed models. RESULTS: About 10% of the population lived less than 2 hours from the hospital, and more than half lived over 4 hours away, with variable access depending on climatic conditions. Only the four health centres located near the paved road had referral times to the hospital within 1 hour. Referral time remained the main barrier limiting the number of referrals despite health system strengthening efforts. The addition of two new referral centres is estimated to triple the population living within 2 hours from a centre with better emergency care capacity and nearly double the number of expected referrals. CONCLUSION: This study demonstrates how adapting geographic accessibility modelling methods to local scales can occur through improving the precision of travel time estimates and pairing them with data on health facility use.

Integrating Health Systems and Science to Respond to COVID-19 in a Model District of Rural Madagascar.

There are many outstanding questions about how to control the global COVID-19 pandemic. The information void has been especially stark in the World Health Organization Africa Region, which has low per capita reported cases, low testing rates, low access to therapeutic drugs, and has the longest wait for vaccines. As with all disease, the central challenge in responding to COVID-19 is that it requires integrating complex health systems that incorporate prevention, testing, front line health care, and reliable data to inform policies and their implementation within a relevant timeframe. It requires that the population can rely on the health system, and decision-makers can rely on the data. To understand the process and challenges of such an integrated response in an under-resourced rural African setting, we present the COVID-19 strategy in Ifanadiana District, where a partnership between Malagasy Ministry of Public Health (MoPH) and non-governmental organizations integrates prevention, diagnosis, surveillance, and treatment, in the context of a model health system. These efforts touch every level of the health system in the district-community, primary care centers, hospital-including the establishment of the only RT-PCR lab for SARS-CoV-2 testing outside of the capital. Starting in March of 2021, a second wave of COVID-19 occurred in Madagascar, but there remain fewer cases in Ifanadiana than for many other diseases (e.g., malaria). At the Ifanadiana District Hospital, there have been two deaths that are officially attributed to COVID-19. Here, we describe the main components and challenges of this integrated response, the broad epidemiological contours of the epidemic, and how complex data sources can be developed to address many questions of COVID-19 science. Because of data limitations, it still remains unclear how this epidemic will affect rural areas of Madagascar and other developing countries where health system utilization is relatively low and there is limited capacity to diagnose and treat COVID-19 patients. Widespread population based seroprevalence studies are being implemented in Ifanadiana to inform the COVID-19 response strategy as health systems must simultaneously manage perennial and endemic disease threats.

Networks of Care in Rural Madagascar for Achieving Universal Health Coverage in Ifanadiana District.

Health care is most effective when a patient's basic primary care needs are met as close to home as possible, with advanced care accessible when needed. In Ifanadiana District, Madagascar, a collaboration between the Ministry of Public Health (MoPH) and PIVOT, a non-governmental organization (NGO), fosters Networks of Care (NOC) to support high-quality, patient-centered care. The district's health system has three levels of care: community, health center, district hospital; a regional hospital is available for tertiary care services. We explore the MoPH/PIVOT collaboration through a case study which focuses on noteworthy elements of the collaboration across the four NOC domains: (I) agreement and enabling environment, (II) operational standards, (III) quality, efficiency, and responsibility, (IV) learning and adaptation. Under Domain I, we describe formal agreements between the MoPH and PIVOT and the process for engaging communities in creating effective NOC. Domain II discusses patient referral across levels of the health system and improvements to facility readiness and service availability. Under Domain III the collaboration prioritizes communication and supervision to support clinical quality, and social support for patients. Domain IV focuses on evaluation, research, and the use of data to modify programs to better meet community needs. The case study, organized by the domains of the NOC framework, demonstrates that a collaboration between the MoPH and an NGO can create effective NOC in a remote district with limited accessibility and advance the country's agenda to achieve universal health coverage.

Short- and long-term humoral immune response against Yersinia pestis in plague patients, Madagascar.

BACKGROUND: Plague, a fatal disease caused by the bacillus, Yersinia pestis, still affects resources-limited countries. Information on antibody response to plague infection in human is scarce. Anti-F1 Ig G are among the known protective antibodies against Y. pestis infection. As a vaccine preventable disease, knowledge on antibody response is valuable for the development of an effective vaccine to reduce infection rate among exposed population in plague-endemic regions. In this study, we aim to describe short and long-term humoral immune responses against Y. pestis in plague-confirmed patients from Madagascar, the most affected country in the world. METHODS: Bubonic (BP) and pneumonic plague (PP) patients were recruited from plague- endemic foci in the central highlands of Madagascar between 2005 and 2017. For short-term follow-up, 6 suspected patients were enrolled and prospectively investigated for kinetics of the anti-F1 IgG response, whereas the persistence of antibodies was retrospectively studied in 71 confirmed convalescent patients, using an ELISA which was validated for the detection of plague in human blood samples in Madagascar. RESULTS: Similarly to previous findings, anti-F1 IgG rose quickly during the first week after disease onset and increased up to day 30. In the long-term study, 56% of confirmed cases remained seropositive, amongst which 60 and 40% could be considered as high- and low-antibody responders, respectively. Antibodies persisted for several years and up to 14.8 years for one individual. Antibody titers decreased over time but there was no correlation between titer and time elapsed between the disease onset and serum sampling. In addition, the seroprevalence rate was not significantly different between gender (P = 0.65) nor age (P = 0.096). CONCLUSION: Our study highlighted that the circulating antibody response to F1 antigen, which is specific to Y. pestis, may be attributable to individual immune responsiveness. The finding that a circulating anti-F1 antibody titer could persist for more than a decade in both BP and PP recovered patients, suggests its probable involvement in patients' protection. However, complementary studies including analyses of the cellular immune response to Y. pestis are required for the better understanding of long-lasting protection and development of a potential vaccine against plague.

Reconciling model predictions with low reported cases of COVID-19 in Sub-Saharan Africa: insights from Madagascar.

COVID-19 has wreaked havoc globally with particular concerns for sub-Saharan Africa (SSA), where models suggest that the majority of the population will become infected. Conventional wisdom suggests that the continent will bear a higher burden of COVID-19 for the same reasons it suffers from other infectious diseases: ecology, socio-economic conditions, lack of water and sanitation infrastructure, and weak health systems. However, so far SSA has reported lower incidence and fatalities compared to the predictions of standard models and the experience of other regions of the world. There are three leading explanations, each with different implications for the final epidemic burden: (1) low case detection, (2) differences in epidemiology (e.g. low R 0 ), and (3) policy interventions. The low number of cases have led some SSA governments to relaxing these policy interventions. Will this result in a resurgence of cases? To understand how to interpret the lower-than-expected COVID-19 case data in Madagascar, we use a simple age-structured model to explore each of these explanations and predict the epidemic impact associated with them. We show that the incidence of COVID-19 cases as of July 2020 can be explained by any combination of the late introduction of first imported cases, early implementation of non-pharmaceutical interventions (NPIs), and low case detection rates. We then re-evaluate these findings in the context of the COVID-19 epidemic in Madagascar through August 2020. This analysis reinforces that Madagascar, along with other countries in SSA, remains at risk of a growing health crisis. If NPIs remain enforced, up to 50,000 lives may be saved. Even with NPIs, without vaccines and new therapies, COVID-19 could infect up to 30% of the population, making it the largest public health threat in Madagascar for the coming year, hence the importance of clinical trials and continually improving access to healthcare.

Molecular and serological evidence of flea-associated typhus group and spotted fever group rickettsial infections in Madagascar.

BACKGROUND: Rickettsiae are obligate intracellular bacteria responsible for many febrile syndromes around the world, including in sub-Saharan Africa. Vectors of these pathogens include ticks, lice, mites and fleas. In order to assess exposure to flea-associated Rickettsia species in Madagascar, human and small mammal samples from an urban and a rural area, and their associated fleas were tested. RESULTS: Anti-typhus group (TGR)- and anti-spotted fever group rickettsiae (SFGR)-specific IgG were detected in 24 (39%) and 21 (34%) of 62 human serum samples, respectively, using indirect ELISAs, with six individuals seropositive for both. Only two (2%) Rattus rattus out of 86 small mammals presented antibodies against TGR. Out of 117 fleas collected from small mammals, Rickettsia typhi, a TGR, was detected in 26 Xenopsylla cheopis (24%) collected from rodents of an urban area (n = 107), while two of these urban X. cheopis (2%) were positive for Rickettsia felis, a SFGR. R. felis DNA was also detected in eight (31%) out of 26 Pulex irritans fleas. CONCLUSIONS: The general population in Madagascar are exposed to rickettsiae, and two flea-associated Rickettsia pathogens, R. typhi and R. felis, are present near or in homes. Although our results are from a single district, they demonstrate that rickettsiae should be considered as potential agents of undifferentiated fever in Madagascar.

Prediction of cervical infiltration in Stage II endometrial cancer by different preoperative evaluation techniques (D&C, US, CT, MRI).

OBJECTIVE: Our clinical practice for FIGO Stage II endometrial cancer consists of Wertheim's radical hysterectomy as first choice of treatment. The evaluation of patients is based on D&C. The accuracy of this preoperative staging method is examined here. METHODS: Twenty-nine patients with endometrial cancer with suspected cervical involvement (FIGO Stage II) based on endocervical curettage underwent Wertheim's radical hysterectomy between January 1, 1989 and December 31, 2001 at the Gynaecological Department of the National Institute of Cancer, Budapest, Hungary. In all cases surgico-pathological staging was performed to examine the accuracy of preoperative D&C and to find out whether radical surgery was necessary in all patients and how the preoperative evaluation of patients should be improved. RESULTS: Out of 29 patients who underwent Wertheim's hysterectomy the pathological examination found primary cervical cancer in two patients. These two patients were eliminated from further evaluation. Out of the remaining 27 patients only eight (29.6%) had cervical involvement of endometrial cancer documented by a pathologic review on the hysterectomy specimen. Extrauterine disease was documented in one of the patients with cervical infiltration (1/8) and in one in the cervix-negative group (1/19). Ovarian spread was found in the first case and ovarian infiltration with penetration of the tumour into the parametric tissue in the second case. According to the FIGO classification 18 (66.6%) patients had less extensive disease and two (7.4%) had more extensive disease. Only 26% of the patients (7/27) had surgical findings consistent with the Stage II disease. CONCLUSION: We can conclude that "overtreatment" seems to have occurred in 19 patients, whose cervical infiltration by endometrial cancer could not be proved by pathological staging. It can also be assessed that understaging took place in two cases, which can be explained by two reasons; we did not make use of preoperative imaging techniques since US was applied in six patients, CT in 16 and the most accurate, MRI, on three patients only. The other possible reason, which can point out the bad efficacy of the imaging techniques as well, could be that a major part of the patients received preoperative AL treatment, which could also have influenced the cervical progression. This is possible, but has not been proved. The difference in the number of cervical infiltrations in the group of patients who received preoperative radiotherapy and in the group where they did not, is not significant (p = 0.9742), and infiltration of the endometrium was present in all cases. In the future, proper selection of imaging modalities can improve the staging of gynaecological disorders and preclude unnecessary procedures. In endometrial cancer cases US, especially with the use of TVUS, is often considered to be the primary imaging approach. However, in patients where ultrasound is suboptimal, where there is a large tumour present or the result of imaging studies will directly influence the choice of therapy and guide therapy planning then the higher accuracy of MRI warrants its use. CT is of use in the later stages of disease; differentiation between Stage I and II is difficult and CT is limited in the assessment of myometrial invasion.

[Transtubular potassium gradient in the diagnosis of potassium metabolism disorders]. / A transtubularis káliumgradiens jelentósége a kálium-anyagcsere rendellenességeinek diagnosztikájában.

The transtubular potassium gradient (TTKG) is a simple physiologically based clinical test to study the renal excretion of potassium. This article reviews the most important physiological changes influencing TTKG, the hypokalaemia and hyperkalaemia, the effect of mineralocorticoids, alkalosis, action of diuretics among other drugs etc. The authors studied the abnormalities of TTKG occurring in clinical conditions (renal patients with nephrotic edema, "dry" patients with renal diseases, liver cirrhosis associated with ascites, and primary hyperaldosteronism) and compare them to the results obtained in healthy people. They consider the test to be useful in the recognition of conditions with hypoaldosteronism (including the various types of pseudohypoaldosteronisms and aldosterone resistance) and hyperaldosteronism as well as renal diseases, in accordance with the data published in the literature. On the basis of their own results, they found the method of determination of TTKG informative and helpful also when investigating the site of actions and the effect mechanisms of the diuretics.

[Hypophosphatemic oncogenic osteomalacia]. / Hypophosphataemiával járó onkogén osteomalacia.

The first case of oncogen osteomalacia in Hungary is reported, to draw the attention of the medical profession to it and to present the new data about its pathomechanism. Pathological hip fracture caused by hypophosphataemic osteomalacia due to isolated renal phosphate wasting was found in a previously healthy 19 years old sportsman. In spite of daily 1.5 micrograms calcitriol treatment and phosphate supplementation, hypophosphataemia persisted for 13 years and he needed regular indometacin medication for his bone pain. During that time an 1.5 cm gingival tumour was found and radically removed. The serum phosphate level returned to normal in a few hours after the operation (preoperative 0.51, after 2, 4 and 8 hours 0.61, 0.68 and 0.79 mmol/l respectively), and remained normal without calcitriol. The histological examination showed epulis with fibroblast and vascular cell proliferation, which has never been previously reported in connection with oncogenic osteomalacia. The pain resolved after 3 months and the bone density became normal in one year. Oncogenic osteomalacia must be considered in every case presenting with atypical hypophosphataemic osteomalacia. Careful dental examination is needed also in the course of search for the underlying tumour. Every tumour-like growth, even the common epulis, has to be operated radically and serum phosphate monitored in the postoperative period in all such cases.

[Hyperkalemias]. / Hyperkalaemiák.

Hyperkalaemia is a frequent electrolyte disturbance connected with new knowledge and practical routine. It is developed by the disorders of the "external balance" (potassium [K] intake and output) as well as the "internal balance" (distribution of K in the extracellular and intracellular fluid compartments). Factors playing a role in it are: the upright posture, physical activity and hyperosmolality. In the hormonal regulation of K metabolism first of all beta adrenergic agents, insulin and aldosterone have significance; the first two mainly in the internal balance. Hyperkalaemia is occurring especially frequently in renal patients (in acute and chronic renal insufficiency, in dialyzed persons) in patients with diabetes, in adrenal insufficiency (Addison's disease, in selective hypoaldosteronisms and in pseudohypoaldosteronisms) in renal tubular acidosis as well as in response to various drugs (ACE inhibitors, angiotensin receptor antagonists, beta blocking agents, potassium sparing diuretics, NSAID's, anticoagulants etc.). Interactions between illness and drugs as well as between drugs and hormones may have outstanding importance in the development of hyperkalaemia. Physical activity carried out in the upright posture in the presence of hyperosmolality (water restriction together with salt or/and glucose loading) developing in pharmacological hypoaldosteronism accompanied with insulin deficiency, may be especially dangerous with respect to hyperkalaemia. To avoid life-threatening hyperkalaemia it is necessary 1. to stop cardiotoxicity with calcium; 2. to enhance K uptake by the cells by bicarbonate, insulin and beta adrenergic agents; and 3. to remove abnormal quantities of K from the body by enemas and/or ion exchange resins. The quickest and best way of treatment of hyperkalaemia is haemodialysis.

Patterns of potassium wasting in response to stepwise combinations of diuretics in nephrotic syndrome.

OBJECTIVE: To study the urinary potassium wasting patterns when the decreasing effectiveness of diuretics during repeated administrations are counterbalanced by stepwise increases of doses and combinations of them. PATIENTS: Eleven patients with renal edema. Seven patients suffered from advanced nephrotic syndrome and 4 patients were "forme fruste". METHODS: Urinary excretions and serum levels of potassium, sodium, creatinine, osmoles were determined; specific renal functions, glomerular filtration rate (GFR) fractional excretion of potassium (FE(K)), transtubular potassium gradient (TTKG) and free water reabsorption (TcH2O) were calculated. Nine different intervention-induced changes were followed daily: furosemide (FSD) alone, FSD with chlorthalidone (CTN), "low dose" and "high dose" potassium sparing drugs (PSD), FSD with CTN and "low dose" or "high dose" PSD, and "no drug" as well as "postdiuretic" periods with or without PSD. RESULTS: TTKG significantly decreased in response to FSD. It elevated during FSD with CTN, but remained lower than the baseline. The normal correlation between urinary potassium excretion (UKV) and TTKG became distorted under FSD. UKV and FE(K) were slightly increased by FSD and more markedly when given FSD together with CTN, probably because "distal volume flow" was elevated. In the "postdiuretic" periods TTKG increased, but this was reversed by PSD. In response to PSD, TTKG and UKV decreased, but both were elevated when combining with FSD + CTN. CONCLUSIONS: FSD caused relatively small potassium loss, because the enhanced "distal volume flow" was counterbalanced by a decrease of TTKG. FSD may have had a potassium secretion inhibitory influence as well. Potassium loss and TTKG were enhanced during coadministration of CTN, and decreased by PSD. "Postdiuretic rebound" increase of TTKG was reversed by PSD.

High-dose phosphate treatment leads to hypokalemia in hypophosphatemic osteomalacia.

The mechanism of the decrease in plasma potassium induced by phosphate treatment was investigated in a 24-year-old hypertensive patient with hypophosphatemic osteomalacia, who was the youngest of four patients, belonging to a 23 number kindred of five generations. Parameters of potassium, sodium, calcium, and phosphate metabolism as well as specific renal functions have been studied in the basal state and during administration of graded doses of phosphate (500-6000 mg). Progressive hypokalemia developed during phosphate treatment. An inverse correlation was found between plasma potassium and doses of phosphate (plasma potassium = -0.2 g phosphate + 3.9 r = -0.49; p < 0.05; N = 21). A renal route of potassium loss was suspected, but could not be confirmed as potassium excretion did not increase although sodium excretion was augmented [basal sodium output: 56.7 mmol/24 h; phosphate treatment: 153 mmol/24 h (p < 0.05)]. Transtubular potassium gradient (TTKG) also decreased and an inverse correlation was found between TTKG and doses of phosphate (r = -0.37; p < 0.02; N = 38). Decrease of TTKG was possibly the result of suppressed K+ secretion. It was concluded that potassium loss occurred by a non-renal (intestinal) route in phosphate-induced hypokalemia. Although major hazards of treatment of hypophosphatemic osteomalacia with phosphate and calcitriol are secondary hyperparathyroidism and vitamin D intoxication, potassium loss also should be kept in mind.

[Nephrogenic diabetes insipidus]. / Nephrogen diabetes insipidus.

The syndrome of polyuria and polydipsia is practically identical in three very different disorders (central diabetes insipidus, nephrogenic diabetes insipidus, primary polydipsia). In congenital nephrogenic diabetes insipidus both the thirst mechanism and the production of the antidiuretic hormone are intact, but the hormone is ineffective in the kidney. The acquired form of the disease is caused most frequently by tubulointerstitial and urinary tract obstructive disorders as well as among the several drugs, lithium. In the differential-diagnosis the results of determinations related to the nomograms of normal interrelationships between osmolality and vasopressin in urine and plasma are used, besides the classical Carter-Robbins and indirect dehydration (Miller) tests. It has been postulated recently that in many cases the resistancy toward vasopressin is not absolute and these partially vasopressin sensitive patients can be treated successfully by thiazide, and potassium sparing compounds, antiprostaglandin pain killers (non-steroid antiinflammatory drugs) and first of all dDAVP as well as combinations of these preparations.